Project Summary/Abstract Systemic lupus erythematosus (SLE) is an autoimmune-mediated inflammatory disease of unknown etiology. The pathologic hallmarks of SLE are altered immune responses to autoantigens with autoantibody production and subsequent tissue injury, with CD4+ T cells as critical drivers of the B cell dependent autoantibody response. Conversely, little is known about the role of CD8+ T cells in the development of lupus, despite the fact that these cells comprise a significant portion of peripheral lymphocytes and play a major role in immune responses via cytotoxicity and cytokine production. Recent studies have shown that expansion of memory CD8+ T cells occurs in patients with SLE, an expansion that is correlated with disease activity, findings that we have replicated in preliminary studies. The mechanism that underlies this expansion, and its implications, are unknown. Logic dictates that the answer to the former question is chronic immune stimulation by autoantigens. Yet previous studies have revealed that T cell proliferation and IL-2 production in response to T cell receptor (TCR) triggering is diminished in human lupus, suggesting a defective, not enhanced, autoantigen-driven response and T cell expansion in disease. Alternatively, but not mutually exclusively, memory CD8+ T cell expansion in lupus could occur independently of antigenic stimulation. Indeed, IL-15 has been emerged as a key cytokine for the maintenance (homeostasis) of memory CD8+ T cells by promotion of cell proliferation and expansion. Thus, the expansion of memory CD8+ T cells in lupus could be driven, at least in part, by IL-15. This notion is supported by the findings of an increase in serum IL-15 levels and expression of IL-15 by monocytes in patients with SLE. What then are the pathological implications of such cell expansion in lupus? IL-15 can promote effector functions of CD8+ T cells including cytokine production and cytotoxicity. Thus, we hypothesize that IL-15 induces expansion of memory CD8+ T cells with pathological implications in patients with SLE. This hypothesis will be addressed with the following specific aims: 1) Determine the mechanisms for memory CD8+ T cell expansion in patients with SLE; 2) Investigate the pathological implications of memory CD8+ T cell expansion in patients with SLE; and 3) Prospectively investigate whether expansion of memory CD8+ T cells correlates with a variety of clinical and biological parameters of SLE. Proving this hypothesis has implications for understanding the pathogenesis of lupus, and potentially could lead to new targets for therapeutic intervention.Project Narrative The goal of the current proposal is to investigate the roles of memory CD8+ T cells and the cytokine IL-15 in the pathogenesis of human lupus. The results of this study will not only aid our understanding of lupus, but will also potentially lead to better diagnostic tools as well as disease monitoring and treatment.